1. Evidence-Based Medicine Changing Practice Dr Feagan’s Top 10 Clinical Trials c/o Dr Brian Feagan Presented and updated by Barrett Levesque MD, Director, Academic Research

2. The RCT at Age 50 32% 68% Streptomycin Placebo British MRC Working Party. BMJ. 1948;669-782 British MRC Trial 1948 % Improvement at 6 months in Patients with Pulmonary Tuberculosis %

3. The Ascending of the RCT 1948- # of RCTs 1x10 4

4. The RCT at Age 50 A Gold Standard for Evidence Based Medicine Reduction of Bias

5. The RCT A Gold Standard for Evidence Based Medicine Control of Confounders TPA 62 (52, 70) Streptokinase N=9841 N=10,396 62 (52, 70) 130 (111,144)130 (113,144) 73 (62, 85)73 (62, 86) 164 (115, 232)165 (120, 230) Age (yr) Systolic Blood Pressure (mmHg) Heart Rate (beats/min) Time to Treatment (min)

7. #10:Hydrocortisone Therapy for UC % Response Truelove SC, Witts LJ. Br Med J. 1955 Oct 29;(4947):1041-8. HydrocortisonePlacebo 30.2% 11.1% p= 0.02

8. #9 NCCDS: The Trial You Love to Hate Circa 1980 Induction therapy/maintenan ce of remission 4 arms(Placebo, AZA, prednisone, SPS) Overwhelming in its’ complexity Almost impossible to read! Summers et al Gastroenterology 1979

9. #8 Nobel Prize 20--?

11. Chu CQ et al. British Journal of Rheumatology 1992;31:653-661

12. #7 Pentasa Dose -Finding What You Don’t Know Can Hurt (Your Patients!)

13. 5-ASA

14. Corticosteroids: Induction of Remission

15. 5-ASA: Induction of Remission

16. “in contrast to these findings a nearly identical second trial of this same formulation of mesalamine for treatment of active Crohn’s Disease failed to show significant superiority over placebo” Singleton Letter Singleton Gastroenterology 1993

17. 5-ASA for Induction of Remission: A Mega Analysis 3 RCT’s for induction with a similar design Pooled original data n= 311 Placebo vs 304 5-ASA p=0.04 Hanauer S, Stromberg U, DDW Abstract 2308; 2001.  63  45 Change in CDAI from Baseline

18. #6 NACSG Part I and II (Change is Coming!)

19. Methotrexate

20. % Response Feagan. N Eng J Med. 1995 Feb 2;332 (5):292-7 0 25 19.1% 39.4% p=0.025 PlaceboMTX 50 MTX Part I Results: Remission

21. Results: Time to Relapse % Remission Weeks Since Randomization Methotrexate Placebo P=0.044

22. Maini RN et al 1998 Arthritis Rheum. 41:1552 Rationale of Combination Infliximab and MTX 100 75 50 25 0 (% of patients) Infliximab dose (mg/kg) 1 3 10 Antibodies to Infliximab Infliximab Infliximab + MTX

23. #5 Oh Canada! ( eh ) (This Buds for you!)

24. Corticosteroids in IBD Toxicity

25. Budesonide

26. Budesonide Absorption and Metabolism Systemic circulation 10% to 20% Liver ~100% 60% to 70% absorbed in the ileal and ileocecal area CYP3A4 80% to 90% first-pass metabolism Metabolites with negligible glucocorticosteroid affinity

27. Budesonide for Active Crohn’s Disease Patients in Remission (%) n = 66 Placeb o 3 mg n = 67 9 mg n = 61 15 mg n = 64 Greenberg et al. N Engl J Med. 1994;331:836-841. Budesonide

28. Budesonide vs Prednisolone: Induction of Remission for Active CD *p=0.22; † p<0.001; ‡ p=0.12. Rutgeerts et al. N Engl J Med. 1994;331:842-845. Treatment (weeks) Prednisolone 40 mg qd tapered q 2 wk to 25 mg (n=88) Budesonide 9 mg qd x 8 wk tapered to 6 mg (n=88) 24810 Patients in Remission (%) (CDAI  150) 100 80 60 40 20 0 * † ‡ ‡

29. Budesonide vs Mesalamine: Induction of Remission *p=0.001; † p=0.004; ‡ p<0.001. Thomsen et al. N Engl J Med. 1998;339:370-374. Patients in Remission (%) CDAI  150 Treatment (weeks) Budesonide 9 mg qd (n=93) Mesalamine 2 g bid (n=89)10080 60 40 20 0 2481216 * † ‡

30. #4 Causing a Traffic Jam in UC !

31. Endothelial and Leukocyte Adhesion:  4 Integrins  1  7  44 Leukocyte membrane glycoproteins  1 and  7 subunits Interact with endothelial ligands VCAM-1, fibronectin, and MAdCAM-1 Mediate leukocyte adhesion and trafficking Springer TA. Cell. 1994;76:301–314. Butcher EC, et al. Science. 1996;272:60-66.

32. Ligand for  4  7 is MAdCAM Animal models show that ACT-1 selectively blocks trafficking of  4  7 positive lymphocytes to the gut Raises possibility of gut specific immune modulation Striking benefit in cotton top tamarin model Alpha 4 Beta 7 MAdCAM -1 ACT -1 1. Hesterberg PE. et al. Gastroenterology. 1996 Nov;111(5):1373-802. Podolsky. et al JCI,1993;(92):372-80 Background

33. % Remission Overall p=0.030 15% 34% 33% p=.021 p=.015 Feagan BG. Gastroenterology 2003. Clinical Remission at Week 6

34. 0 5 10 15 20 25 30 35 Placebo0.5 mg/kg2.0 mg/kg Clinical Remission Week 6 % Remission Overall P = 0.030 15% 34% 33% P =.021 P =.015 Feagan BG. et al N Engl J Med. 2005;352(24):2499-507.

35. Vedolizumab Phase III: Study Design Induction Phase Week 0 – Week 6 Maintenance Phase Week 6 – Week 52 Cohort 1 Blinded Induction N=374 Cohort 1 complete? Cohort 2 Open-Label Induction N=521 Screening, Enrollment Placebo N=149 VDZ N=225 VDZ N=521 Week 6: Responder? Placebo N=126 VDZ Q8 wks N=122 VDZ Q4 wks N=125 Placebo N=149 VDZ N=373 No Yes No Yes Week 52 Assess- ments *Responders began tapering regimen at 6 weeks; others, as soon as a clinical response was achieved. Corticosteroid Tapering* Feagan, B.G. et al New Engl J Med 2013

36. Clinical Response, Clinical Remission, Mucosal Healing at 6 Weeks, ITT Population % P<0.0001 P=0.0010  21.7 11.6, 31.7  11.5 4.7, 18.3  16.1 6.4, 25.9 P=0.0010 95% CI: Feagan BG et al New Engl J Med 2013

37. Primary and Secondary Outcomes Through 52 Weeks, ITT Population %  26.1  29.1  32.8  28.5  32.0  36.3  11.8  15.3  17.6  31.4 *** ** *** * *P<0.05. **P<0.01. ***P<0.0001 n:727073 Feagan BG et al New Engl J Med 2013

38. #3 Tipping Convention on Its Head!

39. Early Combined Immunosuppressive Therapy With Infliximab and Azathioprine Versus Conventional Therapy in Active Early Crohn’s Disease Newly diagnosed Crohn’s disease (n=129) Step-up (n=64) Steroids Top-down (n=65) IFX (0/2/6) + AZA + IFX + AZA MTX Steroids IFX + AZA + (episodic) IFX Steroids D’Haens G, et al. Lancet. 2008 The primary endpoints were remission (CDAI <150) and off steroids at months 6 and 12

40. Early Combined Immunosuppressive Therapy With Infliximab and Azathioprine Versus Conventional Therapy in Active Early Crohn’s Disease (CDAI REMISSION) D’Haens, Lancet 2008 At week 104, 100% of top-down patients were using azathioprine or methotrexate, compared with 76% of step-up patients.

41. Early Combined Immunosuppressive Therapy With Infliximab and Azathioprine Versus Conventional Therapy in Active Early Crohn’s Disease Conventional Management Early Combined Immunosuppression P=0.0307 Time to Relapse by Treatment Group D’Haens, Lancet 2008 Percent Relapse Free

42. Early Combined Immunosuppressive Therapy With Infliximab and Azathioprine Versus Conventional Therapy in Active Early Crohn’s Disease Proportion of Patients Receiving Azathioprine or Methotrexate Over Time by Treatment Group 0 26 52 78 104 Weeks Since Randomization 0 26 52 78 104 Weeks Since Randomization Early Combined Immunosuppression Conventional Management D’Haens, Lancet 2008

43. Early Combined Immunosuppressive Therapy With Infliximab and Azathioprine Versus Conventional Therapy in Active Early Crohn’s Disease Points % of Patients ‡ † Endoscopic healing was scored in 5 ileal and colonic segments as follows: 0=no ulcers, 1= aphthoid ulcers, 2=larger ulcers, 3= ulcerated stenosis. ‡ p<.001 Early Combined Immunosuppression (n=24) Conventional Management (n=20) ‡ ‡ Mucosal Healing D’Haens, Lancet 2008

44. #2 SONIC Goes Boom!

45. SONIC:Clinical Remission Without Corticosteroids at Week 26 30 45 57 0 20 40 60 80 100 Proportion of Patients (%) AZA + placeboIFX + placeboIFX+ AZA p<0.001 p=0.009p=0.022 52/17075/16996/169 Sandborn et al. AJG 2008. 103 Issue: s1 S408-S455 Abstract #1117

46. Immunogenicity Status at Week 30 Centocor, data on file n=89n=106n=120 98

47. #1 The Curious Case of COMMIT

48. COMMIT :Schematic Overview of Trial Design MTX Placebo Infliximab 5 mg/kg x 8 weekly Treatment success Off prednisone CDAI <150 Treatment success Success week 14 & maintenance of remission Randomization Week -1 0 1 2 3 4 14 46 50 MTX 10 10 20 20 25 (weekly mg) Prednisone tapering

49. P=0.63 Weeks Since Randomization Proportion of Patients with Treatment Success % Success

50. % Antibody Positive at Endpoint % 4.0 20.4

51. Effect of Methotrexate on Trough Infliximab Concentration % Detectable Infliximab 86.0 74.1

52. Median Trough Concentration of Infliximab at Endpoint Micrograms per litre 6.35 3.75

53. COMMIT :Effect of Infliximab Trough Concentration on Treatment Success % Success72.3 52.4

54. Top 10! 10)Truelove –Cortisone for UC 1955 9) Summers -NCCDS 1979 8)Vanderventer- Infliximab 7) Singleton - 5 -ASA 1994 6)NACSG I and II- MTX for CD 1995, 2000 5)Greenberg - Bud induction 1994 4) Feagan -MLN-O2 for UC 2005/2013 3 ) D ’ Haens- Top Down 2007 2) SONIC 1)COMMIT ––––––––––––––––––––––––––

55. Take Away Messages 1)RCTs are gold standard for clinical medicine (Truelove) 2)NCCDS data are a cornerstone for our current therapeutic algorithms in CD (Summers) 3)Case reports can lead to bigger things (Vanderventer) 4)Publication bias does exist and you can be influenced by it (Singleton/Hanauer) 5)MTX has an important role in the management of Crohn’s disease (NACSG) 6)Canada ’ s IBD Community has changed the world (Greenberg Bud) 7)Selective Inhibition of WBC trafficking is a novel therapeutic strategy in UC (Feagan MLNO2) 8)Early Combined Immunosuppression may be a preferred strategy in CD(D ’ Haens) 9)SONIC has changed the world (Colombel) 10)Even Evidence- base medicine zealots can be biased (COMMIT)